Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase, being in insulin receptor superfamily. Protein structure, from N terminal to C terminal, is successively: extracellular domain, transmembrane domain and intracellular tyrosine kinase domain. Normal ALK protein is mainly expressed in the central nervous system and the peripheral nervous system. The expression level of ALK gene in human body decreases with the development of brain, especially in mature brain tissue. However, in other systems especially in hematopoietic system the expression of ALK has not yet been found. This shows that the expression and distribution thereof have certain regional characteristics.
Normally, human ALK gene encodes 1602 amino acids and 200 kDa type I transmembrane protein ALK, but the gene is usually dormant. In the case of fusion with other genes, ALK gene can become a very powerful oncogene. At present, it has been found that genes that can fuses ALK gene include nuclear phosphoprotein (NPM, anaplastic large cell lymphoma ALCL), echinoderm microtubule associated protein-like 4 genes (EML4, non-small cell lung cancer NSCLC), tropomyosin 3 gene (TPM3, inflammatory myofibroblastic tumor IMT) and so on (Nat. Rev. Cancer, 2008, 8, 11-23; Nat. Rev. Cancer, 2013, 13, 685-700; Expert Opin. Ther. Pat., 2014. 24(4): p. 417-42).
In non-small cell lung cancer, the fusion with EML4 mainly occurs. The incidence rate of fused gene (EML4-ALK) in NSCLC is 4%-7%. With the deepening of research on non-small cell lung cancer (NSCLC) in molecular biology, personalized treatment based on molecular marker (biomarker) has been from the laboratory to the clinic, and has made great progress in the clinical treatment of patients with advanced non-small cell lung cancer. This means that besides traditional histopathological classification, NSCLC can be subjected to the molecular phenotype classification according to different expression level of different biomarkers in specific patients. NSCLC patients are tested for relevant biomarkers prior to treatment. In clinical practice, doctors can conduct targeted therapies based on the phenotypic characteristics of tumor molecules to thereby enhance therapeutic efficiency. In this context, research and development of new drugs have become the focus of anticancer drug research with driving genes associated with tumorigenesis and development of tumors or coding proteins thereof as targets.
At present, the U.S. Food and Drug Administration (FDA) has approved small molecule inhibitors Crizotlnib (J. Thorac. Oncol., 2010.5 (12): p. 2044-6) developed by Pfizer, Ceritinib (J. Med. Chem., 2013.56 (14): p. 5675-90) developed by Novartis for listing. Alectinib (Cancer Lett., 2014.351 (2): P. 215-21) developed by Chugai PharmaceutlCal has been approved for listing in Japan. However, clinical studies show that some patients have been resistant to Crizotinib, and the bioavailability of Crizotinib remains to be improved. Ceritinib can target patients with Crizotinib resistance or intolerance, while Alectinib is only marketed in Japan and is still in clinical trials in Europe and the United states. As a result, alternative compounds are needed in clinical practice.
